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Biomedical subjects

I J Kullo

Publications and source records attributed to I J Kullo.

12 recordsLinked to original sources
PubMed2007

Urinary albumin excretion is associated with impaired flow- and nitroglycerin-mediated brachial artery dilatation in hypertensive adults.

We investigated whether the urinary albumin/creatinine ratio (UACR), a measure of albuminuria, is associated with non-invasive measures of arterial function in hypertensive adults without known coronary heart disease (CHD) or stroke. UACR was measured in the first voided morning urine sample in 469 non-Hispanic white hypertensive individuals (mean age 62.2+/-9.8 years, 41% men) belonging to hypertensive sibships. High-resolution ultrasonography of the brachial artery was used to assess flow-mediated dilatation (FMD)--an endothelium-dependent response--and nitroglycerin-mediated dilatation (NMD)--an endothelium-independent response. Because of skewed distribution, UACR was log transformed after addition of 0.1. The association of log (UACR+0.1) with FMD and NMD, before and after adjustment for CHD risk factors, serum creatinine, and hypertension medication and statin use was assessed using linear regression analyses. In univariable analyses, variables associated with lower FMD were greater age, male sex, history of smoking, lower high-density lipoprotein (HDL) cholesterol, higher serum creatinine and higher log (UACR+0.1); variables associated with lower NMD were greater age, male sex, higher systolic blood pressure, lower HDL cholesterol, higher serum creatinine and higher log (UACR+0.1). In separate stepwise multivariable regression analyses that adjusted for conventional CHD risk factors, serum creatinine and hypertension medication and statin use, higher log (UACR+0.1) was associated with lower brachial artery FMD (P=0.035) and NMD (P=0.0002). These findings highlight the association of increased urinary albumin excretion with impaired vascular reactivity in hypertensive individuals.

Albuminuria↗
PubMed2000

Vascular actions of brain natriuretic peptide: modulation by atherosclerosis and neutral endopeptidase inhibition.

OBJECTIVES: We sought to define the vascular actions of the cardiac hormone brain natriuretic peptide (BNP) on cellular proliferation and cyclic guanosine monophosphate (cGMP) in human aortic vascular smooth muscle cells (HAVSMCs). Secondly, we investigated BNP and acetylcholine (ACh) vasorelaxations in aortic rings from normal and atherosclerotic rabbits in the presence and absence of long-term oral inhibition of neutral endopeptidase (NEP). BACKGROUND: The vascular actions of BNP are not well defined, despite the presence of its receptor in vascular smooth muscle and the upregulation of NEP, the ectoenzyme that degrades BNP, in the vascular wall in atherosclerosis. METHODS: HAVSMCs stimulated with fetal calf serum (FCS) were pulsed with bromodeoxyuridine (BrdU) with and without BNP. The HAVSMCs were incubated in the presence and absence of BNP to assess cGMP. Vasorelaxations to BNP and ACh were assessed in rings in normal and atherosclerotic rabbits in the presence and absence of long-term oral inhibition of NEP, together with assessment of atheroma formation. RESULTS: FCS-stimulated BrdU uptake in HAVSMCs was suppressed with BNP. BNP potentiated cGMP in HAVSMCs. BNP resulted in potent vasorelaxation in normal isolated aortic rings, which were impaired in atherosclerotic versus normal rabbits and preserved with NEP inhibition, which also decreased atheroma formation. Relaxations to ACh, which were also impaired in atherosclerosis, were preserved with inhibition of NEP. CONCLUSIONS: We conclude that BNP potently inhibits vascular smooth muscle cell proliferation and potentiates the generation of cGMP. BNP potently relaxes the normal rabbit aorta, and this response is impaired in atherosclerosis but preserved with inhibition of NEP, together with a reduction in atheroma formation and preservation of relaxations to ACh.

Acetylcholine↗
PubMed2000

Novel risk factors for atherosclerosis.

In the past several years, evidence has accumulated that factors other than conventional risk factors may contribute to the development of atherosclerosis. Conventional risk factors predict less than one half of future cardiovascular events. Furthermore, conventional risk factors may not have the same causal effect in different ethnic groups in whom novel risk factors may have a role. These newer risk factors for atherosclerosis include homocysteine, fibrinogen, impaired fibrinolysis, increased platelet reactivity, hypercoagulability, lipoprotein(a), small dense low-density lipoprotein cholesterol, and inflammatory-infectious markers. Identification of other markers associated with an increased risk of atherosclerotic vascular disease may allow better insight into the pathobiology of atherosclerosis and facilitate the development of preventive and therapeutic measures. In this review, we discuss the evidence associating these factors in the pathogenesis of atherosclerosis, the mechanism of risk, and the clinical implications of this knowledge.

Arteriosclerosis↗
PubMed1999

Intracardiac leiomyomatosis: echocardiographic features.

Intravenous leiomyomatosis is a histologically benign smooth-muscle tumor arising from either a uterine myoma or the walls of a uterine vessel with extension into veins. Echocardiographic features of two cases of intravenous leiomyomatosis with extensive spread into the right-sided cardiac chambers and pulmonary arteries are described. Both patients were middle-aged women, with prior history of hysterectomy 12 and 10 years earlier who presented with cardiac symptoms and signs. Distinctive echocardiographic features include 1) elongated mobile masses extending from the veins of the lower body, including inferior vena cava and azygos vein; 2) multiple venous attachments or metastases; and 3) filling of venous vessels and right-heart chambers. Intracardiac leiomyomatosis should be considered in a female patient presenting with an extensive mass in the right-sided cardiac chambers.

Echocardiography, Transesophageal↗
PubMed1998

Vulnerable plaque: pathobiology and clinical implications.

PURPOSE: To review the pathobiology and clinical implications of vulnerable coronary atherosclerotic plaques and to discuss the identification of vulnerable plaques and mechanisms of plaque stabilization. DATA SOURCES: English-language articles in the MEDLINE database that were published from 1966 to the present, identified by using the terms atherosclerotic plaque, myocardial revascularization, and plaque stabilization. Selected references cited in identified articles were reviewed. STUDY SELECTION: Experimental, clinical, and basic research studies related to coronary atherosclerotic plaques. DATA SYNTHESIS: Rupture at the site of a vulnerable atherosclerotic plaque is the most frequent cause of acute coronary syndromes. Typically, such plaque does not cause high-grade stenosis and has a large lipid core and a thin fibrous cap that is often infiltrated by inflammatory cells. Mechanical stresses contribute to plaque vulnerability, and certain triggers may cause plaque disruption directly. The most important consequence of plaque rupture is thrombosis. No method reliably identifies plaques prone to rupture. The reduction of coronary events by lipid-lowering agents despite only modest luminal changes suggests that these agents have a plaque-stabilizing effect. Surgical or percutaneous revascularization does not address the basic biology of coronary atherosclerosis and therefore may have little effect on plaque vulnerability. CONCLUSIONS: Improved understanding of the biology of atheromatous plaques has led to the concept of plaque vulnerability. Identification and stabilization of vulnerable plaques are important new directions in the treatment of coronary atherosclerosis. The relative benefits of aggressive medical therapy aimed at plaque stabilization should be compared with those of revascularization in the management of chronic coronary artery disease.

Animals↗
PubMed1998

Ex vivo gene transfer of endothelial nitric oxide synthase to atherosclerotic rabbit aortic rings improves relaxations to acetylcholine.

Cholesterol feeding results in impaired endothelium dependent vasorelaxation. The role of nitric oxide in this process is unclear. The aim of this study was to evaluate the role of nitric oxide in cholesterol-induced vasomotor dysfunction by examining the effect of overexpression of eNOS in the hypercholesterolemic rabbit aorta on vascular reactivity. Vascular rings from the thoracic aorta of hypercholesterolemic rabbits were exposed ex vivo either to an adenoviral vector encoding endothelial nitric oxide synthase (AdeNOS) or Escherichia coli beta Galactosidase (AdbetaGal). Transgene expression was examined by histochemistry for beta galactosidase, immunohistochemistry for eNOS and cyclic GMP measurements and vasomotor studies were performed. Transgene expression was found to localize to the endothelium and adventitia. cGMP levels were significantly greater in AdeNOS compared to AdbetaGal transduced rings. Acetylcholine mediated relaxation was significantly impaired in cholesterol fed rabbits and was markedly improved by overexpression of eNOS. These results suggest that reduced NO bioavailability observed in cholesterol-induced vascular dysfunction can be partially overcome by eNOS gene transfer.

Acetylcholine↗
PubMed1997

Adventitial gene transfer of recombinant endothelial nitric oxide synthase to rabbit carotid arteries alters vascular reactivity.

BACKGROUND: Adventitial gene transfer may serve as a tool to study vascular biology and may have therapeutic potential. We investigated the hypothesis that adenovirus-mediated transfer of the gene for endothelial nitric oxide synthase (eNOS) to the adventitia would alter vascular reactivity. METHODS AND RESULTS: Rabbit carotid arteries were surgically isolated and adenoviral vectors encoding eNOS (AdeNOS) or beta-galactosidase instilled into the periarterial sheath at a concentration of 1 x 10(10) pfu/mL. Arteries were harvested 4 days later for immunostaining, NOS enzymatic assay, measurement of cGMP, and vasomotor studies. Transgene expression in the adventitia was confirmed by histochemistry for beta-galactosidase and immunostaining for eNOS with a monoclonal antibody. Calcium-dependent NOS enzymatic activity and cGMP levels were significantly greater in the AdeNOS-transduced arteries. Maximal contractions to phenylephrine (10(-5) mol/L) were diminished in the AdeNOS-transduced arteries (4.6+/-0.2 versus 5.6+/-0.2 g; P<.05), but in the presence of the eNOS inhibitor N(G)-monomethyl-L-argininc (3x10(-4) mol/L) there was no difference between the two groups (7.1+/-0.2 versus 7.5+/-0.3 g; P=NS). Relaxations to calcium ionophore obtained during submaximal contractions to phenylephrine were significantly enhanced in the AdeNOS-transduced arteries (-log EC50, 7.77+/-0.08 versus 7.45+/-0.07; P<.02). CONCLUSIONS: We conclude that eNOS gene transfer to the adventitia alters vascular reactivity, as demonstrated by diminished contractile responses to phenylephrine and enhanced relaxations to calcium ionophore. This may represent a therapeutic strategy for vascular diseases characterized by decreased bioavailability of NO.

1-Methyl-3-isobutylxanthine↗
PubMed1997

Expression and function of a recombinant endothelial nitric oxide synthase gene in porcine coronary arteries.

OBJECTIVES: Direct gene transfer of exogenous nitric oxide synthase, with the subsequent increase in nitric oxide production, could represent a potential therapeutic strategy in the treatment of vascular proliferative disorders. The goal of the present study was to determine if porcine coronary arteries could be transduced with an adenoviral vector encoding endothelial nitric oxide synthase (Ad.CMVeNOS) resulting in functional expression. METHODS AND RESULTS: Segments of porcine right coronary artery were exposed for 1 h at 37 degrees C to either replication-deficient adenovirus encoding bovine endothelial nitric oxide synthase (Ad.CMVeNOS, 5 x 10(9) pfu/ml) or control adenovirus encoding Escherichia coli beta-galactosidase (Ad.CMVLacZ, 5 x 10(9) pfu/ml). Immunohistochemistry with a monoclonal antibody specific for nitric oxide synthase (NOS) demonstrated recombinant gene expression in both the endothelial and adventitial layers of Ad.CMVeNOS transduced coronaries with only endogenous NOS confirmed in the endothelium of Ad.CMVLacZ arteries. Coronary arteries transduced with Ad.CMVeNOS yielded 517 +/- 110 (mean +/- S.E.M.) nM/ng nitrite while vessels transduced with Ad.CMVLacZ yielded 126 +/- 84 nM/ng (P < 0.05, n = 6). Isometric tension recording, following prostaglandin F2 alpha constriction, documented a reduced tension in Ad.CMVeNOS transduced coronaries, compared to matched Ad.CMVLacZ coronaries (6.10 +/- 1.08 g vs. 8.45 +/- 1.19 g, respectively, P = 0.05, n = 8). This tension differential was eliminated with prior incubation in NG-monomethyl-L-arginine (L-NMMA, 10(-4) M). The EC50 for calcium ionophore relaxation of Ad.CMVeNOS coronary arteries was reduced compared to Ad.CMVLacZ (-7.90 +/- 0.03 logM vs. -7.26 +/- 0.11 logM, respectively, P < 0.05, n = 8). CONCLUSIONS: These studies demonstrate successful transfer of endothelial nitric oxide synthase into porcine coronary arteries as verified by histochemical localization of recombinant protein with an increase of nitric oxide release as demonstrated by enhanced nitrite production and an alteration in vasomotor function.

Adenoviridae↗
PubMed1997

Expression and function of recombinant endothelial NO synthase in coronary artery smooth muscle cells.

Smooth muscle cells (SMCs) play a key role in the pathogenesis of vascular diseases. The objectives of this study were to determine whether transfer of recombinant endothelial nitric oxide synthase (eNOS) gene to porcine coronary artery smooth muscle cell (CSMCs) would result in expression of a functional enzyme and to assess the effect of expression of eNOS on cell proliferation. CSMCs were transduced in vitro with adenoviral vectors encoding cDNA for eNOS (AdeNOS) and beta-galactosidase (Ad beta Gal). In contrast to Ad beta Gal- or sham-transduced cells, CSMCs transduced with AdeNOS stained positive with the NADPH-diaphorase stain, acquired calcium-dependent NOS activity (measured by the conversion of [3H]L-arginine to [3H]L-citrulline), had increasing cyclic 3',5' cGMP levels with increasing concentrations of the vector, and produced increased amounts of nitrite. cGMP production by AdeNOS-transduced cells was augmented by increasing intracellular levels of the eNOS cofactor tetrahydrobiopterin. CSMCs transduced with AdeNOS showed diminished serum-stimulated DNA synthesis as measured by thymidine uptake. Cell proliferation was diminished in AdeNOS-transduced CSMCs as assessed by cell counts 3 and 6 days after serum stimulation of quiescent CSMCs. The present study demonstrates that adenovirus-mediated gene transfer of eNOS to CSMCs results in the expression of a functional enzyme whose activity can be augmented by increasing intracellular levels of tetrahydrobiopterin. Expression of recombinant eNOS in CSMCs results in inhibition of serum-stimulated DNA synthesis and cell proliferation. These findings imply that eNOS gene transfer to SMCs may be a unique mode of increasing local NO production in the arterial wall.

Adenoviridae↗
PubMed1997

Enhanced endothelium-dependent relaxations after gene transfer of recombinant endothelial nitric oxide synthase to rabbit carotid arteries.

We tested the effects of overexpression of the endothelial nitric oxide synthase (eNOS) gene in the normal arterial wall by adenoviral-mediated gene transfer. Rabbit carotid arteries were surgically isolated and exposed to adenoviral vectors encoding eNOS (AdeNOS) or beta-galactosidase (Ad betaGal) on the contralateral side. Vector solutions at a concentration of 1 x 10(10) plaque forming units/mL were instilled for 20 minutes before restoration of flow. Arteries were harvested 4 days later for immunostaining, measurement of cGMP, and vasomotor studies. Endothelium-specific gene transfer was confirmed by staining for beta-galactosidase in the Ad betaGal arteries. Immunostaining of en face endothelial cell imprints from AdeNOS-transduced arteries with a monoclonal antibody to eNOS showed increased immunoreactivity. Basal cGMP levels were significantly greater in the AdeNOS-transduced arteries (18.4+/-4.6 versus 4.2+/-0.5 pmol/mg protein; P<.05). Contractions to phenylephrine were significantly reduced in the AdeNOS-transduced arteries (area under curve, 106+/-5 versus 119+/-7; P<.05), but in the presence of the eNOS inhibitor, N(G)-monomethyl-L-arginine (L-NMMA, 3 x 10(-4) mol/L), there was no difference between the two (area under curve, 148+/-5 versus 153+/-6; P=NS). Relaxations to acetylcholine obtained during submaximal contractions to phenylephrine were significantly enhanced in the AdeNOS-transduced arteries (EC50, 7.45+/-0.05 versus 7.23+/-0.03; P<.05). We conclude that overexpression of eNOS in the endothelium results in diminished contractile responses, as well as enhanced endothelium-dependent relaxations. These findings imply a possible role for vascular eNOS gene transfer in the treatment of vasospasm and endothelial dysfunction.

Animals↗
PubMed1995

Right ventricular dysplasia: the Mayo Clinic experience.

OBJECTIVE: To determine the initial clinical manifestations and echocardiographic features of right ventricular dysplasia as encountered in a major cardiovascular referral center in the United States. DESIGN: We conducted a retrospective study of cases of right ventricular dysplasia diagnosed at the Mayo Clinic between January 1978 and January 1993. MATERIAL AND METHODS: In an institutional data-base search, we identified 20 patients with right ventricular dysplasia. Echocardiographic, electrophysiologic, Holter monitoring, cardiac catheterization, and endomyocardial biopsy results were analyzed. The mean duration of follow-up was 7 years. RESULTS: In the 12 female and 8 male patients (mean age, 30 years; range, 3 to 60), the initial manifestations of right ventricular dysplasia included ventricular arrhythmia (45%), congestive heart failure (25%), heart murmur (10%), asymptomatic (10%), complete heart block (5%), and sudden death (5%). First-order relatives were affected in 30% of the patients. Ventricular tachycardia with morphologic features of left bundle branch block was inducible in seven of nine patients. On Holter monitoring, all but 2 of 15 patients studied had frequent ventricular ectopic activity (Lown grade 2 or more). Characteristic fatty infiltration of the myocardium was present in 7 of 13 right ventricular biopsy specimens. Inordinate right ventricular enlargement was present in 60% of the patients at first echocardiographic assessment and in two other patients on follow-up assessment. Variable left ventricular involvement was noted in 50% of the cases. During the follow-up period, four patients died: two died suddenly, one died of congestive heart failure, and one died of respiratory failure after a coronary artery bypass operation. Of the 16 living patients, 8 are doing well, 3 have an implanted cardiac defibrillator, 3 are receiving antiarrhythmic agents, and 2 have undergone cardiac transplantation because of progressive biventricular failure. CONCLUSION: Patients with right ventricular dysplasia have varied initial manifestations and a high frequency of serious cardiovascular symptoms and complications.

Adolescent↗